Post Hoc Subgroup Analysis of the
HEART2D Trial Demonstrates Lower
Cardiovascular Risk in Older Patients
Targeting Postprandial Versus
ITAMAR RAZ, MD1
ANTONIO CERIELLO, MD2
PETER W. WILSON, MD3
CHAKIB BATTIOUI, PHD4
ERIC W. SU, PHD4
LISA KERR, MSPH4
CATE A. JONES, PHD4
ZVONKO MILICEVIC, MD5
SCOTT J. JACOBER, DO4
OBJECTIVE—To identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction
on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial sub-
groups with treatment difference.
RESEARCH DESIGN AND METHODS—In 1,115 type 2 diabetic patients who had
suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin
strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular
event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospi-
talization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We
used the classification and regression tree (CART) to identify baseline subgroups with potential
event. In the subgroup aged .65.7 years (prandial, n = 189; basal, n = 210), prandial patients
had a significantly longer time to first event and a lower proportion experienced a first event (n =
56[29.6%]vs. n=85 [40.5%]; hazard ratio0.69 [95%CI 0.49–0.96];P=0.029),despitesimilar
CONCLUSIONS—Older type 2 diabetic AMI survivors may have a lower risk for a subse-
quent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia.
Diabetes Care 34:1511–1513, 2011
cular Outcomes in Patients With Type 2
Diabetes Mellitus (HEART2D) trial wasto
assess the time to first cardiovascular
event for two glucose-lowering strategies
in type 2 diabetic patients who had
survived an acute myocardial infarction
(AMI) (1). The trial was stopped early for
he primary objective of the Hyper-
glycemia and Its Effect After Acute
Myocardial Infarction on Cardiovas-
futility, partly because of fewer than ex-
pected cardiovascular events.
We conducted post hoc analyses us-
ing the classification and regression tree
(CART) technique (2) to determine pa-
tient subgroups for which the two strate-
event. CART sifts through numerous co-
variates to determine which covariate,
and at what cut point, best splits the data.
RESEARCH DESIGN AND
METHODS—Details of the HEART2D
trial have been previously published (1).
bined adjudicated cardiovascular event
(cardiovascular death, nonfatal MI, non-
fatal stroke, coronary revascularization,
or hospitalization for acute coronary syn-
drome) was compared in 1,115 type 2 di-
abetic patients after an AMI hospital
admission. Patients were randomly as-
signed to prandial glycemia control
meal glycemia control (twice-daily NPH
or once-daily insulin glargine) (1) and
participated a mean of 2.7 years post–
CART estimated the best subgroup
with respect to difference in primary out-
come. Decision trees in each arm used a
“time to cardiovascular event” target and
45 covariate predictors based on baseline
A 10-fold crossvalidation technique de-
termined the right-sized tree and built a
model with good generalization prior to
testing the subgroups. Previously pub-
lished statistical analyses (1) were per-
formed to determine treatment differences
for the intent-to-treat population. Baseline
HDL interactions were tested using a gen-
eralized linear model.
RESULTS—CART produced a one-
level decision tree and identified age at
the cut point of .65.7 years as the best
predictor of time to first cardiovascular
event. Among the patients screened (1),
451 comprised the subgroup aged .65.7
years and 52 patients did not continue,
resulting in 399 intent-to-treat popula-
tion patients (prandial, n = 189; basal,
n = 210). Ninety-four (49.7%) of the
prandial and 91 (43.3%) of the basal pa-
tients did not continue, and 214 patients
completed the trial (prandial, n = 95
[50.3%]; basal, n = 119 [56.7%]).
There were no significant differences
in baseline characteristics between arms,
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
From the1Department of Internal Medicine, Hadassah Hospital, Jerusalem, Israel; the2Institut d’Investiga-
cions Biomèdiques August Pi Sunyer and Centro de Investigación Biomédica en Red de Diabetes y Enfer-
medades Metabólicas Asociadas, Barcelona, Spain; the3Department of Medicine, Cardiology Division,
Emory University School of Medicine, Atlanta, Georgia;4Lilly Research Laboratories, Eli Lilly and Com-
pany, Indianapolis, Indiana; and5Lilly Regional GMBH, Eli Lilly and Company, Vienna, Austria.
Corresponding author: Scott J. Jacober, email@example.com.
Received 17 December 2010 and accepted 6 April 2011.
DOI: 10.2337/dc10-2375. Clinical trial reg. no. NCT00191282, clinicaltrials.gov.
L.K. is currently affiliated with Pharmaceutical Product Development, Morrisville, North Carolina.
© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
licenses/by-nc-nd/3.0/ for details.
care.diabetesjournals.orgDIABETES CARE, VOLUME 34, JULY 2011
C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c h
B R I E F R E P O R T
including A1C, diabetes therapies, prior
ically relevant measures, but HDL choles-
prandial control (means 1.0 6 0.3 vs.
1.0 6 0.2 mmol/L; medians 1.0 6 0.3 vs.
0.9 6 0.2 mmol/L; P = 0.013).
In the subgroup aged .65.7 years,
prandial arm patients experienced a sig-
nificantly lower time to first cardiovascu-
proportion experienced a first cardiovas-
cular event (n = 56 [29.6%] vs. n = 85
[40.5%]; hazard ratio 0.69 [95% CI
0.49–0.96]; P = 0.029). Risk for individ-
ual cardiovascular events comprising the
primary outcome did not differ signifi-
cantly between arms (Fig. 1). The effect
of baseline HDL prior to the index event
was not statistically significant for the pri-
mary outcome. The hazard ratio for all-
cause death, cardiovascular death, or
nificance. In the subgroup aged #65.7
years, arms did not differ significantly
for the primary outcome (n = 118
[32.1%] vs. n = 96 [27.6%]; 1.24 [0.95–
1.63]; P = 0.11).
There were no differences in overall
glycemia or in combined measures of
premeal or postprandial glycemia. Mean
significantly lower with the basal arm
(7.87 6 0.32 vs. 6.71 6 0.22 mmol/L;
P = 0.001), and 2-h postprandial blood
glucose excursion was significantly lower
with prandial control (0.17 6 0.24 vs.
1.21 6 0.15 mmol/L; P , 0.0001) be-
cause of significantly lower morning and
noon excursions. Nocturnal hypoglyce-
mia rates were significantly higher in the
basal arm ([means 6 SEM] 0.15 6 0.04
vs. 0.61 6 0.10 per patient per episode
per year; P , 0.001), whereas overall
and severe hypoglycemia rates and total
insulin dose did not differ significantly.
BMI was significantly higher in the pran-
dial arm (30.08 6 0.29 vs. 29.21 6 0.27
kg/m2; P = 0.015), but lipid profiles,
blood pressure levels, left ventricular
ejection fraction, and QTc interval were
CONCLUSIONS—The premise of the
HEART2D trial was that the two major
A1C components, prandial and fasting/
premeal glycemia, may affect cardiovas-
cular risk differently (3). Recent trials
(4–6) demonstrated that intensive glu-
cose therapy lowered A1C but with no
significant difference in major cardiovas-
reported a modest effect of total glycemic
exposure on cardiovascular risk, older-
patient-subgroup reports demonstrated
with type 2 diabetes may have a lower risk
for subsequent cardiovascular events with
insulin therapy targeting prandial versus
fasting/premeal glycemia, despite similar
Older patients may be susceptible to
glycemic and nonglycemic mechanisms
Figure 1—Kaplan-Meier survival curve of the percentage of HEART2D patients in the subgroup aged .65.7 years who did not experience a first
for acute coronary syndrome) vs. days in the trial by insulin strategy. Solid black line, prandial insulin arm (targeted prandial glycemia control);
dashed black line, basal insulin arm (targeted fasting/premeal glycemia).
DIABETES CARE, VOLUME 34, JULY 2011care.diabetesjournals.org
Cardiovascular risk in older patients: HEART2D
associated with the postprandial period, Download full-text
which may increase cardiovascular risk.
The more pronounced postprandial ex-
cursions in the older-subgroup basal
arm may indicate increased exposure to
postprandial-state abnormalities of oxida-
tive stress, inflammation, endothelial dys-
function (8,9), a prothrombotic state
characterized by elevated platelet and co-
agulation activation and inhibited fibrino-
lysis (10,11), and less vasodilation caused
by lower insulinemia (12). Abnormalities
of sympathetic function, vasoactive pep-
tide action, and meal carbohydrate con-
tent may predispose older patients to
postprandial hypotension and cardiovas-
cular events (13,14).
On the other hand, the significantly
lower fasting blood glucose and signifi-
cantly greater nocturnal hypoglycemia in
the basal versus prandial arm may have
contributed to the difference in cardio-
vascular outcomes. Lower fasting blood
glucose and greater nocturnal hypoglyce-
mia in the older subgroup compared with
the total HEART2D trial population (1)
may explain the disparity between the
that its post hoc nature with multiple
testing on many variables renders it only
hypothesis generating. Additional limita-
tions include the fact that the follow-up
period may be inadequate to evaluate
cardiovascular outcomes, the primary
outcome included two subjective out-
comes, patients had advanced cardiovas-
cular disease, and dropout was high.
Most people with diabetes in devel-
oped countries are aged $65 years, and
prevalence in that age-group worldwide
dial glycemia control was associated with
lower cardiovascular risk than fasting/
premeal glycemia control for older AMI
survivors with type 2 diabetes warrants
Acknowledgments—The HEART2D study
E.W.S., Z.M., C.A.J., and S.J.J. are employees
was an employee and shareholder during the
trial. I.R. serves on speaker bureaus for Eli Lilly
and Novo Nordisk; advisory boards for Roche,
Novo Nordisk, AstraZeneca, and Bristol-Myers
Squibb; and as a consultant for AstraZeneca/
Bristol-Myers Squibb and Andromeda. A.C.
serves on speaker bureaus and advisory boards
potential conflicts of interest relevant to this
article were reported.
I.R. contributed to discussion and wrote,
reviewed, and edited the manuscript. A.C.
contributed to discussion and reviewed and
edited the manuscript. P.W.W. reviewed and
edited the manuscript. C.B. and E.W.S. re-
searched data, contributed to discussion, and
reviewedand editedthe manuscript. C.A.J. con-
tributed to discussion and wrote, reviewed, and
edited the manuscript. L.K., Z.M., and S.J.J.
wrote, reviewed, and edited the manuscript.
The authors thank Byron Hoogwerf, MD (Eli
Lilly and Company) for his criticalreview of the
manuscript, and Jinghui Hu, PhD (Eli Lilly and
Company) and Helen You, MS (inVentiv Clini-
cal Solutions, LLC) for statistical programming.
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cardiovascular outcomes in type 2 di-
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